TOPS-ester is a topical drug selected for development for it's unique ability to compartmentalize within skin cells and express antioxidant activity that limits oxidant mediated pathologies including psoriasis, sunburn, skin aging and skin cancer. The objective of this proposal is to use a non-invasive electron paramagnetic resonance (EPR) spectroscopy and imaging technique to monitor TOPS-ester (i.e. diethyl 2,2,6,6-tetramethyl-1-oxyl-4-piperidene succinate, or DETOPS) in human skin for the purpose of guiding the prophylactic and therapeutic treatment of skin disease. The DETOPS ester is a paramagnetic molecule and hence can be conveniently studied using EPR spectroscopy. Based on our preliminary data, we propose that after DETOPS penetrates cells of the epidermis and dermis, the succinate-ester moiety of the molecule is hydrolyzed by intracellular esterases to succinate anions; thereby facilitating intracellular retention of negatively charged carboxylate derivatives of DETOPS in the skin. The specific aims are to demonstrate the feasibility of distinguishing the difference between DETOPS and Tempol in their temporal distribution in human skin. The EPR measurements will be performed using the newly developed topical EPR imaging instrumentation for humans at the Johns Hopkins University. The skin penetration, compartmentalization and metabolism of the DETOPS in the forearm skin of human volunteers will be investigated using spatially resolved pharmacokinetic imaging data. It is expected that this preliminary study will lead to the evaluation of the therapeutic potential of the DETOPS formulation for the prevention and treatment of a variety of skin pathophysiological disorders.